Angiogenesis is a biological process of generating new blood vessels in a tissue or organ, and under normal physiological conditions, humans or animals generate new blood vessels only in very specific restricted situations. The angiogenesis occurs through a series of sequential steps including reconstructing vessels and generating new capillary vessels through decomposition of a vascular basement membrane by a proteolytic enzyme, proliferation and migration of the vascular endothelial cells that constitute vessel walls, and formation of a tube (a blood-vessel) by differentiating the vascular endothelial cells.
Further, the angiogenic process is strictly regulated by various negative and positive regulatory factors (Folkman and Cotran., Int. Rev. Exp. Patho., 16, 207˜248, 1976), but if the angiogenesis is not normally regulated, it causes pathological disorders such as diabetic retinopathy, rheumatoid arthritis, inflammation, endometriosis, age-related vision deterioration, psoriasis, and hemangioma.
When major diseases associated with angiogenesis are classified, the diseases may be divided into inflammatory diseases such as arthritis, ophthalmological diseases such as diabetic retinopathy, dermatological diseases such as psoriasis, and cancer. Examples of an ophthalmological disease caused by angiogenesis include diseases such as macular degeneration, diabetic retinopathy, as a complication of diabetes, in which capillary vessels in the retina invade the vitreous body, and as a result, an eye becomes blind, retinopathy of prematurity, and neovascular glaucoma, and several millions of people globally lose their eyesight each year due to these diseases. In addition, an autoimmune disorder acts as a cause of arthritis, but it is known that chronic inflammation occurring in the synovial cavity induces angiogenesis as arthritis develops, and arthritis is a disease occurring when new capillary vessels invade the joints and the cartilage is destroyed. Furthermore, psoriasis is also a chronic proliferative disease occurring on skin, and since a lot of blood needs to be supplied for rapid proliferation of the disease, angiogenesis cannot help but to actively occur. Accordingly, the discovery of a material inhibiting neovascularization may also be widely used for the treatment of diseases such as diabetic retinopathy, rheumatoid arthritis, inflammation, endometriosis, age-related vision deterioration, psoriasis, and hemangioma, which are diseases associated with neovascularization, so that currently, the academic and industrial fields have been continuously conducting research and development on a novel material having these functions.
Furthermore, abnormal angiogenesis serves to supply nutrients and oxygen required for the growth and proliferation of a tumor, and new capillary vessels invading a tumor provide metastasizing cancer cells with an opportunity to enter the blood circulation system, thereby allowing the cancer cells to metastasize. Accordingly, studies on the mechanism of angiogenesis and development of a material capable of suppressing angiogenesis have been a focus of attention in the prevention and treatment of cancer, and recently, while the fact that the inhibition of tumor angiogenesis can effectively suppress the growth and development of a tumor and can prolong a patient's life in an animal cancer model and a human clinical experiment has been proven, studies on the development of an angiogenesis inhibitor have been actively conducted.
About 200 angiogenesis inhibitors developed until now have been reported, and the angiogenesis inhibitors can be largely classified into four angiogenesis inhibitor types which respectively play a role in the mechanism of decreasing the activity of a specific angiogenesis promoting factor, the mechanism of inducing the growth inhibition or apoptosis of vascular endothelial cells, the mechanism of inhibiting the action of indirect factors regulating an angiogenesis promoting factor or an endothelial cell survival factor, and the mechanism of increasing the activity of angiogenesis inhibitors present in vivo, and in particular, angiogenesis inhibitors such as angiostatin, endostatin, PK5, and prothrombin kringle 2 are well known (O'Relly, M. S. et al. Cell., 79, 315328, 1994; Lee. T. H., Biol. Che., 273, 28805˜28812, 1998). However, even though various angiogenesis inhibitors in the related art are already known, the inhibitor has problems in that it is difficult to maintain an excellent activity for a long period of time, pharmaceutical characteristics are low, and the inhibitor may be easily denatured, so that there is a need for developing a new neovascularization inhibiting material.
Meanwhile, neo-N-methylsansalvamide (NMSSV), which is a cyclic pentadepsipeptide of the present invention, is a cyclic pentadepsipeptide in which the binding sequences of sansalvamide A (San A), N-methylsansalvamide, four constituent amino acids, and one hydroxy acid are different, and there is nothing known about the angiogenesis inhibition activity, which has not been reported from studies on sansalvamide A, N-methylsansalvamide, and homologues organically synthesized by using sansalvamide A and N-methylsansalvamide as a basic cyclic structure.